Abstract
Primary liver cancer is predicted to be the sixth most common cancer and the fourth leading cause of cancer mortality worldwide. Recent studies identified nonalcoholic fatty liver disease (NAFLD) as the underlying cause in 13–38.2% of patients with hepatocellular carcinoma unrelated to viral hepatitis and alcohol abuse. NAFLD progresses to nonalcoholic steatohepatitis (NASH), which increases the risk for the development of liver fibrosis, cirrhosis, and hepatocellular carcinoma. NAFLD is characterized by dysregulation of lipid metabolism. In addition, lipid metabolism is effected not only in NAFLD, but also in a broad range of chronic liver diseases and tumor development. Cancer cells manipulate a variety of metabolic pathways, including lipid metabolism, in order to build up their own cellular components. Identifying tumor dependencies on lipid metabolism would provide options for novel targeting strategies. This review article summarizes the research evidence on metabolic reprogramming and focuses on lipid metabolism in NAFLD, NASH, fibrosis, and cancer. As alternative routes of acetyl-CoA production for fatty acid synthesis, topics on glutamine and acetate metabolism are included. Further, studies on small compound inhibitors targeting lipid metabolism are discussed. Understanding reprogramming strategies in liver diseases, as well as the visualization of the metabolism reprogramming networks, could uncover novel therapeutic options.
Highlights
Primary liver cancer is predicted to be the sixth most common cancer and the fourth leading cause of cancer mortality worldwide in 2018 [1]
Hepatocellular carcinoma (HCC) usually develops within a background of advanced chronic liver diseases, such as chronic infection with hepatitis B virus (HBV), hepatitis C virus (HCV), and alcohol abuse
nonalcoholic fatty liver disease (NAFLD) is tightly associated with the metabolic syndrome, and metabolic reprogramming has been firmly recognized as a hallmark of cancer [4]
Summary
Primary liver cancer is predicted to be the sixth most common cancer and the fourth leading cause of cancer mortality worldwide in 2018 [1]. Recent studies identified nonalcoholic fatty liver disease (NAFLD) as the underlying cause in 13–38.2% of patients with HCC unrelated to virus and alcohol [3]. Cancer cells reprogram a variety of metabolic pathways in order to build up their own cellular components, such as nucleic acids, proteins, and lipids. Activation of lipid synthesis is highly important for rapidly growing cancer cells, because lipids such as phospholipid bilayers are fundamental membrane components enabling cellular proliferation [5]. In a wide variety of tumors, de novo synthesis of fatty acids (FAs) is activated irrespective of the levels of circulating lipids. It has been shown that several signaling pathways in cancer cells can activate de novo FA synthesis, covering more than 93% of triacylglycerol FAs [6]. The current review article provides a background of liver cancer metabolism, focusing on lipid metabolism and targeting strategies for modulating factors and enzymes associated with lipid metabolic pathways
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